The present invention relates to novel pyrazoles, to processes for their preparation and to their use as nematicides and anthelmintics as well as to the intermediates for the preparation of pyrazoles.
Specifically, 3-(2-Thienyl)-5-phenyl-1H-pyrazole has already been disclosed in Zh. Org. Khim., 15(1), 57-63, 1979, and 3-(2-thienyl)-5-(4-methoxyphenyl)-1H-pyrazole has been described in J. Electron Spectrosc. Relat. Phenom., 31(4), 317-21, 1983.
However, it is neither described nor suggested in these publications that the aforesaid compounds have a nematicidal action.
Moreover, a certain kind of insecticidal oxazole or thiazole derivatives have already been disclosed in WO 87/06429, and insecticidal bithienyl derivatives have been ray described in WO 86/05949.
Pyrazoles of the formula (I) 
wherein
R1 represents halogen, C1-6 alkyl, C1-5 haloalkyl, C2-6 alkoxy, C1-4 alkylthio, C2-5 alkenyloxy, C3-5 alkenyloxy, C2-6 (total carbon number) alkoxyalkyl, C2-6 (total carbon number) alkylthioalkyl, C1-5 haloalkoxy, C2-6 (total carbon number) alkoxyalkoxy, hydroxy or optionally substituted phenyl,
R2 represents hydrogen, halogen, C1-5 alkyl, C2-6 (total carbon number) alkoxy-alkyl, C2-6 (total carbon number) alkylthioalkyl, C2-6 (total carbon number) alkylsulfinylalkyl, C2-6 (total carbon number) alkylsulfonylalkyl or C1-5 halo-alkyl,
R3 represents hydrogen, C1-5 alkyl, xe2x80x94COR4, xe2x80x94COOR5, CH(OR6)2, or CH2Si(R7)3,
R4 represents C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, optionally substituted C3-6 cycloalkyl, C2-6 (total carbon number) alkoxyalkyl, C2-6 (total carbon number) alkylthioalkyl, optionally substituted phenyl, C1-5 alkylamino, di-(C1-6 alkyl)amino or optionally substituted phenylamino,
R5 represents C1-7 alkyl,
R6 and R7 represent C1-6 alkyl, and
n is 1, 2 or 3, and when n is 2 or 3, The R1 radicals may be the same or different.
There have now been found novel pyrazoles of the formula (I) 
wherein
R1 represents halogen, C1-6 alkyl, C1-5 haloalkyl, C2-6 alkoxy, C1-4 alkylthio, C2-5 alkenyloxy, C3-5 alkynyloxy, C2-6 (total carbon number) alkoxyalkyl, C2-6 (total carbon number) alkylthioalkyl, C1-5 haloalkoxy, C2-6 (total carbon number) alkoxyalkoxy, hydroxy or optionally substituted phenyl,
R2 represents hydrogen, halogen, C1-5 alkyl, C2-6 (total carbon number) alkoxy-alkyl, C2-6 (total carbon number) alkylthioalkyl, C2-6 (total carbon number) alkylsulfinylalkyl, C2-6 (total carbon number) alkylsulfonylalkyl or C1-5 halo-alkyl,
R3 represents hydrogen, C1-5 alkyl, xe2x80x94COR4, xe2x80x94COOR5, CH(OR6)2, or CH2Si(R7)3,
R4 represents C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, optionally substituted C3-6 cycloalkyl, C2-6 (total carbon number) alkoxyalkyl, C2-6 (total carbon number) alkylthioalkyl, optionally substituted phenyl, C1-5 alkylamino, di-(C1-6 alkyl)amino or optionally substituted phenylamino,
R5 represents C1-7 alkyl,
R6 and R7 represent C1-6 alkyl, and
n is 1, 2 or 3, and when n is 2 or 3,
the corresponding number (n) of R1 radicals may be the same or different.
(i) When R3 is not H, the compound of the above formula (I) can exist as a mixture of the following positional isomers 
wherein R1, R2, R3 and n are as defined above, and 
wherein R1, R2, R3 and n are as defined above.
(ii) When R3 is H, the compound of the above formula (I) can exist as a mixture of the following tautomers: 
wherein R1, R2 and n are as defined above, and 
wherein R1, R2 and n are as defined above.
The compounds of formula (I) can be obtained by a process in which
a) when R3 is hydrogen:
compounds of the formula 
xe2x80x83wherein R1 and n are as defined above,
are reacted with a compound of the formula
NH2xe2x80x94NH2xe2x80x83xe2x80x83(III)
xe2x80x83in the presence of suitable diluent, and if appropriate, in the presence of an acid catalyst, or
b) when R3 is hydrogen
compounds of the formula 
xe2x80x83wherein R1, R2 and n are as defined above,
are reacted with the aforementioned compound of the formula (III) in the presence of
suitable diluent, and if appropriate, in the presence of an acid catalyst, or
c) when R3 is a radical as defined above but other than hydrogen:
compounds of formula 
xe2x80x83wherein R1, R2 and n are as defined above,
are reacted with compounds of the formula
R3xe2x80x94Xxe2x80x83xe2x80x83(VI)
xe2x80x83wherein R3 is a radical as defined above but other than hydrogen, and X is halogen, in the presence of suitable diluent, and if appropriate, in the presence of an acid binding agent, or
d) compounds of the formulae 
xe2x80x83wherein R1, R2, R3 and n are as defined above are oxidized, or
e) when R2 is alkylsulfinylalkyl or alkylsulfonylalkyl:
compounds of the formula 
xe2x80x83wherein R1, R3 and n are as defined above, p is 1, 2 or 3, q is 1, 2, 3, 4 or 5, and 2xe2x89xa6p+qxe2x89xa66, are oxidized.
The compounds of formula (I) according to the present invention have strong nematicidal activities and anthelmintic activities. In particular, they exhibit a very excellent nematicidal and anthelmintic effects as compared with the aforesaid well-known 3-(2-thienyl)-5-phenyl-1H-pyrazole and 3-(2-thienyl)-5-(4- methoxyphenyl)-1H-pyrazole, and also have a good affinity for crops and mammals. Accordingly, the compounds of the present invention are very useful as nematicides and anthelmintics.
In this specification, the xe2x80x9chalogenxe2x80x9d and the halogen in the xe2x80x9chaloalkylxe2x80x9d and the xe2x80x9chaloalkoxyxe2x80x9d means fluoro, chloro, bromo or iodo.
The xe2x80x9calkylxe2x80x9d may be straight-chain or branched, and includes, for example, methyl, ethyl, propyl, isopropyl, n-, iso-, sec- or tert-butyl, n-, iso-, neo- or tert-pentyl, n- or isohexyl, heptyl, octyl, nonyl and decyl.
The xe2x80x9chaloalkylxe2x80x9d may be straight-chain or branched, and includes, for example, chloromethyl, 2-chloroethyl, trifluoromethyl, 2,2,2-trifluoroethyl and 2 2,3,3-tetrafluoropropyl.
The xe2x80x9calkoxyxe2x80x9d may be straight-chain or branched, and includes, for example, ethoxy, propoxy, isopropoxy, n-, iso-, sec- or tert-butoxy, pentyloxy and hexyloxy.
The xe2x80x9calkylthioxe2x80x9d may be straight-chain or branched, and includes, for example, methylthio, ethylthio, propylthio, isopropylthio, and n-, iso-, sec- or tert-butylthio.
The xe2x80x9calkenyloxyxe2x80x9d includes, for example, vinyloxy, allyloxy, 1-propenyloxy, iso-propenyloxy, and 1-, 2- or 3-butenyloxy.
The xe2x80x9calkynyloxyxe2x80x9d includes, for example, propargyloxy. The xe2x80x9calkoxyalkylxe2x80x9d includes, for example, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, n-, iso-, sec- or tert-butoxymethyl, and n-, iso-, sec-, tert- or neo-pentoxymethyl.
The xe2x80x9calkylthioalkylxe2x80x9d includes, for example, methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, n-, iso-, sec- or tert-butylthiomethyl, n-, iso-, sec-, tert- or neo-pentylthiomethyl, and methylthioethyl.
The xe2x80x9chaloalkoxyxe2x80x9d includes, for example, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 2,2,2-trifluoroethoxy and 2,2,3,3-tetrafluoropropyloxy.
The xe2x80x9calkoxyalkoxyxe2x80x9d includes, for example, methoxymethoxy and ethoxymethoxy.
The xe2x80x9calkylsulfinylalkylxe2x80x9d includes, for example, methylsulfinylmethyl, ethylsulfinylmethyl, propylsulfinylmethyl, isopropylsulfinylmethyl and methylsulfinylethyl.
The xe2x80x9calkylsulfonylalkylxe2x80x9d includes, for example, methylsulfonylmethyl, ethylsulfonylmethyl, propylsulfonylmethyl, isopropylsulfonylmethyl and methylsulfonylethyl.
The xe2x80x9ccycloalkylxe2x80x9d includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The xe2x80x9cfluoro-substituted cyclopropylxe2x80x9d includes, for example, 2,2-difluorocyclopropyl.
The xe2x80x9coptionally substituted phenylxe2x80x9d includes, for example, phenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 4-trifluoromethoxyphenyl, (4-fluorophenyl)-phenyl, and (4-trifluoromethylphenyl)phenyl.
The xe2x80x9calkylaminoxe2x80x9d includes, for example, methylamino, ethylamino, propylamino, isopropylamino, n-, iso-, sec- or tert-butylamino, and n-, iso-, sec-, tert- or neo-pentylamino.
The xe2x80x9cdialkylaminoxe2x80x9d includes, for example, dimethylamino, diethylamino and di(n- or iso-)propylamino.
The xe2x80x9coptionally substituted phenylaminoxe2x80x9d includes, for example, phenylamino, 4-fluorophenylamino, 4-chlorophenylamino and 4-trifluoromethylphenylamino.
Among the compounds of the formula (I), according to the invention, preferred compounds are those in which:
R1 represents fluoro, chloro, bromo, iodo, C1-4 alkyl, C1-3 haloalkyl, C2-4 alkoxy, C1-3 alkylthio, C2-3 alkenyloxy, C3-4 alkynyloxy, C2-4 (total carbon number) alkoxyalkyl, C2-4 (total carbon number) alkylthioalkyl, C1-3 haloalkoxy, C2-4 (total carbon number) alkoxyalkoxy, hydroxy, optionally halogen-substituted phenyl or optionally C1-3 alkyl-substituted phenyl,
R2 represents hydrogen, fluoro, chloro, bromo, C1-4 alkyl, C2-4 (total carbon number) alkoxyalkyl, C2-4 (total carbon number) alkylthioalkyl, C2-4 (total carbon number) alkylsulfinylalkyl, C2-4 (total carbon number) alkylsulfonylalkyl or C1-3 haloalkyl,
R3 represents hydrogen, C1-5 alkyl, xe2x80x94COR4, xe2x80x94COOR5, CH(OR6)2 or CH2Si(R7)3,
R4 represents C1-5 alkyl, C1-4 haloalkyl, C2-3 alkenyl, cyclopropyl, fluoro-substituted cyclopropyl, C2-4 (total carbon number) alkoxyalkyl, C2-4 (total carbon number) alkylthioalkyl, optionally halogen-substituted phenyl, optionally C1-3 fluoroalkyl-substituted phenyl, C1-3 alkylamino, di-(C1-4 alkyl)amino or optionally chloro-substituted phenylamino,
R5 represents C1-5 alkyl,
R6 and R7 represent C1-4 alkyl, and
n is 1, 2 or 3, and when n is 2 or 3, R1 radicals may be the same or different.
Particularly preferred compounds of the formula (I) are those in which:
R1 represents fluoro, chloro, bromo, iodo, C1-4 alkyl, fluoro-substituted C1-3 alkyl, C2-3 alkoxy, C1-2 alkylthio, allyloxy, propargyloxy, C2-3 (total carbon number) alkoxyalkyl, C2-3 (total carbon number) alkylthioalkyl, fluoro-substituted C1-3 alkoxy, C2-3 (total carbon number) alkoxyalkoxy, hydroxy or optionally fluoro- or methyl-substituted phenyl.
R2 represents hydrogen, fluoro, chloro, bromo, C1-4 alkyl, C2-3 (total carbon number) alkoxyalkyl, C2-3 (total carbon number) alkylthioalkyl, C2-3 (total carbon number) alkylsulfinylalkyl, C2-3 (total carbon number) alkylsulfonylalkyl or fluoro-substituted C1-3 alkyl,
R3 represents hydrogen, C1-4 alkyl, xe2x80x94COR4, xe2x80x94COOR5, CH(OR6)2 or CH2Si(R7)3,
R4 represents C1-5 alkyl, C1-4 haloalkyl, C2-3 alkenyl, cyclopropyl, fluoro-substituted cyclopropyl, C2-3 (total carbon number) alkoxyalkyl, C2-3 (total carbon number) alkylthioalkyl, optionally fluoro-substituted phenyl, optionally trifluoromethyl-substituted phenyl, C1-2 alkylamino, di-(C1-2 alkyl)amino or optionally para-chloro-substituted phenylamino,
R5 represents C1-4 alkyl,
R6 represents C1-2 alkyl,
R7 represents methyl and
n is 1, 2 or 3, and when n is 2 or 3, R1 radicals may be the same or different.
For example, when 1-(4-chlorophenyl)-3-(2-thienyl)-2-propyn-1-one and hydrazine are used as the starting materials in the above-described method (a) for preparing a compound of formula (I), the preparation method (a) is represented by the following reaction formula: 
For example, when 1-(4-chlorophenyl)-3-(2-thienyl)-1,3-propanedione and hydrazine are used as the starting materials in the above-described method (b) for preparing a compound of formula (I), the preparation method (b) is represented by the following reaction formula: 
For example, when 3-(2-thienyl)-5-(4-chlorophenyl)-1H-pyrazole and acetyl chloride are used as the starting materials in the above-described method (c) for preparing a compound of formula (I), the preparation method (c) is represented by the following reaction formula: 
For example, when 3-(4-chlorophenyl)-5-(2-thienyl)-pyrazoline is used as the starting material and oxidized with the aid of active manganese dioxide in the above-described method (d) for preparing a compound of formula (I), the preparation method (d) is represented by the following reaction formula: 
For example, when 3-(4-chlorophenyl)-4-methylmercapto-methyl-5-(2-thienyl)-1H-pyrazole is used as the starting material and oxidized with the aid of hydrogen peroxide in the above-described method (e) for preparing a compound of formula (I) in which R2 is alkylsulfinyl or alkylsulfonyl, the preparation method (e) is represented by the following reaction formula: 
The compound of formula (II) used as a starting material in the above-described preparation method (a) is a novel compound which has not been described in the literature of the prior art. Generally, the compounds of formula (II) may be prepared, for example, by the preparation method (f) described below.
A method which comprises oxidizing a compound of the formula 
wherein R1 and n are as defined above.
The compounds of the above formula (X),are novel compounds which have not been described in the literature of the prior art, and may be prepared, for example, by the preparation method (g) described below. As compounds of formula (X) in which R1 is hydrogen, 1-(phenyl)-3-(2-thienyl)-2propyn-1-ol is described in J. Org. Chem., 63(4), 1109-1118 (1998), and 1-(4-methoxyphenyl)-3-(2-thienyl)-2-propyn-1-ol is described in J. Chem. Res., Synop. (1), 4-5 (1995).
A method which comprises reacting a compound of the formula 
wherein R1 and n are as defined above, with a compound of the formula 
Typical examples of the compounds of the above formula (X) are as follows:
1-(2-Fluorophenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(2-chlorophenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(2-trifluoromethylphenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(3-chlorophenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(3-methylphenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(4-fluorophenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(4-chlorophenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(4-bromophenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(4-iodophenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(4-methylphenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(4-ethylphenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(4-propylphenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(4-isopropylphenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(4-butylphenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(4-tert-butylphenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(4-trifluoromethylphenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(4-ethoxyphenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(4-propoxyphenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(4-methylmercaptophenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(4-allyloxyphenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(4-propargyloxyphenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(4-methoxymethylphenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(4-ethoxymethylphenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(4-methylmercaptomethylphenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(4-difluoromethoxyphenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(4-trifluoromethoxyphenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-[4-(2,2,2-trifluoroethoxy)phenyl]-3-(2-thienyl)-2-propyn-1-ol,
1-[4-(2,2,3,3-tetrafluoropropyloxy)phenyl]-3-(2-thienyl)2-propyn-1-ol,
1-(4-methoxymethoxyphenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(4-hydroxyphenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(4-phenylphenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-[4-(4-fluorophenyl)phenyl]-3-(2-thienyl)-2-propyn-1-ol,
1-[4-(4-methylphenyl)phenyl]-3-(2-thienyl)-2-propyn-1-ol,
1-(2,4-dichlorophenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(3,4-dichlorophenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(3,5-dichlorophenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(2,6-difluorophenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(2,4-difluorophenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(3,4-difluorophenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(2,4,6-trifluorophenyl)-3-(2-thienyl)-2-propyn-1-ol,
1-(2,4,6-trichlorophenyl)-3-(2-thienyl)-2-propyn-1-ol, and
1-(2,6-difluoro-4-trifluoromethylphenyl)-3-(2-thienyl)-2-propyn-1-ol.
The compounds of the above formula (XI) are also novel compounds which have not been described in the literature of the prior art, and may be prepared, for example, by the preparation method (h) described below.
As compounds of formula (XI) in which R1 is hydrogen, 4-chloro or 4-methoxy, 1-(phenyl)-2-propyn-1-ol, 1-(4-chlorophenyl)-2-propyn-1-ol and 1-(4-methoxyphenyl)-2-propyn-1-ol are described in J. Am. Chem. Soc., 69, 2017 (1947).
A method which comprises reacting a compound of the formula 
wherein R1 and n are as defined above, with a compound of the formula
HCxe2x89xa1Cxe2x80x94Si(CH3)3xe2x80x83xe2x80x83(XIV)
In the above-described preparation method (h), the compounds of formulae (XIII) and (XIV) are compounds which are well known in the field of organic chemistry, and may readily be prepared by any well-known method.
Typical examples of the compounds of the above formula (XI) are as follows:
1-(2-Fluorophenyl)-2-propyn-1-ol,
1-(2-chlorophenyl)-2-propyn-1-ol,
1-(2-trifluoromethylphenyl)-2-propyn-1-ol,
1-(3-chlorophenyl)-2-propyn-1-ol,
1-(3-methylphenyl)-2-propyn-1-ol,
1-(4-fluorophenyl)-2-propyn-1-ol,
1-(4-bromophenyl)-2-propyn-1-ol,
1-(4-iodophenyl)-2-propyn-1-ol,
1-(4-methylphenyl)-2-propyn-1-ol,
1-(4-ethylphenyl)-2-propyn-1-ol,
1-(4-propylphenyl)-2-propyn-1-ol,
1-(4-isopropylphenyl)-2-propyn-1-ol,
1-(4-butylphenyl)-2-propyn-1-ol,
1-(4-tert-butylphenyl)-2-propyn-1-ol,
1-(4-trifluoromethylphenyl)-2-propyn-1-ol,
1-(4-ethoxyphenyl)-2-propyn-1-ol,
1-(4-propoxyphenyl)-2-propyn-1-ol,
1-(4-methylmercaptophenyl)-2-propyn-1-ol,
1-(4-allyloxyphenyl)-2-propyn-1-ol,
1-(4-propargyloxyphenyl)-2-propyn-1-ol,
1-(4-methoxymethylphenyl)-2-propyn-1-ol,
1-(4-ethoxymethylphenyl)-2-propyn-1-ol,
1-(4-methylmercaptomethylphenyl)-2-propyn-1-ol,
1-(4-difluoromethoxyphenyl)-2-propyn-1-ol,
1-(4-trifluoromethoxyphenyl)-2-propyn-1-ol,
1-[4-(2,2,2-trifluoroethoxy)phenyl]-2-propyn-1-ol,
1-[4-(2,2,3,3-tetrafluoropropyloxy)phenyl]-2-propyn-1-ol,
1-(4-methoxymethoxyphenyl)-2-propyn-1-ol,
1-(4-hydroxyphenyl)-2-propyn-1-ol,
1-(4-phenylphenyl)-2-propyn-1-ol,
1-[4-(4-fluorophenyl)phenyl]-2-propyn-1-ol,
1-[4-(4-methylphenyl)phenyl]-2-propyn-1-ol,
1-(2,4-dichlorophenyl)-2-propyn-1-ol,
1-(3,4-dichlorophenyl)-2-propyn-1-ol,
1-(3,5-dichlorophenyl)-2-propyn-1-ol,
1-(2,6-difluorophenyl)-2-propyn-1-ol,
1-(2,4-difluorophenyl)-2-propyn-1-ol,
1-(3,4-difluorophenyl)-2-propyn-1-ol,
1-(2,4,6-trifluorophenyl)-2-propyn-1-ol,
1-(2,4,6-trichlorophenyl)-2-propyn-1-ol, and
1-(2,6-difluoro-4-trifluoromethylphenyl)-2-propyn-1-ol.
The compounds of the above formula (II) are novel compounds which have not been described in the literature of the prior art. 1-(Phenyl)-3-(2-thienyl)-2-propyn-1-one and 1-(4-methoxyphenyl)-3-(2-thienyl)-2-propyn-1-one, which correspond to the compounds of formula (II) wherein R1 is hydrogen or methoxy, are described in Japanese Patent Kokai Publication Sho 56-123904, and the compounds of formula (II) may be prepared by the preparation method described in the aforementioned Japanese Patent Kokai Publication Sho 56-123904.
Typical examples of the compounds of the above formula (II) are as follows:
1-(2-Fluorophenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(2-chlorophenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(2-trifluoromethylphenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(3-chlorophenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(3-methylphenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(4-fluorophenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(4-chlorophenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(4-bromophenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(4-iodophenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(4-methylphenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(4-ethylphenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(4-propylphenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(4-isopropylphenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(4-butylphenyl)-3-(2-thienyl )-2-propyn-1-one,
1-(4-tert-butylphenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(4-trifluoromethylphenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(4-ethoxyphenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(4-propoxyphenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(4-methylmercaptophenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(4-allyloxyphenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(4-propargyloxyphenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(4-methoxymethylphenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(4-ethoxymethylphenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(4-methylmercaptomethylphenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(4-difluoromethoxyphenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(4-trifluoromethoxyphenyl)-3-(2-thienyl)-2-propyn-1-one,
1-[4-(2,2,2-trifluoromethoxy)phenyl]-3-(2-thienyl)-2-propyn-1-one,
1-[4-(2,2,3,3-tetrafluoropropyloxy)phenyl]-3-(2-thienyl)2-propyn-1-one,
1-(4-methoxymethoxyphenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(4-hydroxyphenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(4-phenylphenyl)-3-(2-thienyl)-2-propyn-1-one,
1-[4-(4-fluorophenyl)phenyl]-3-(2-thienyl)-2-propyn-1-one,
1-[4-(4-methylphenyl)phenyl]-3-(2-thienyl)-2-propyn-1-one,
1-(2,4-dichlorophenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(3,4-dichlorophenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(3,6-dichlorophenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(2,6-difluorophenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(2,4-difluorophenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(3,4-difluorophenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(2,4,6-trifluorophenyl)-3-(2-thienyl)-2-propyn-1-one,
1-(2,4,6-trichlorophenyl)-3-(2-thienyl)-2-propyn-1-one, and
1-(2,6-difluoro-4-trifluoromethylphenyl)-3-(2-thienyl)-2-propyn-1-one.
Within the scope of the compound of formula (IV) used as a starting material in the above-described preparation method (b), a compound in which R1 is para-chloro, namely 1-(4-chlorophenyl)-3-(2-thienyl)-1,3-propanedione, is a well-known compound which is disclosed, for example, in J. Amer. Chem. Soc., Vol. 72, 5219 (1950). However, the compounds of formula (IV) may generally be prepared by the preparation method (i) described below.
A method which comprises reacting a compound of the formula
Arxe2x80x94COOxe2x80x94Rxe2x80x83xe2x80x83(XV)
wherein Ar is 
R is C1-6 alkyl, and R1 and n are as defined above, with a compound of the formula 
xe2x80x83wherein Ar is 
xe2x80x83and R1, R2 and n are as defined above.
The above-described method (i) for preparing the compounds of formula (IV) may be carried out according to the procedure described in Organic Synthesis Collective Vol. III, 251.
In the above-described preparation method (i), formula (XV) represent the formula 
wherein R, R1 and n are as defined above, or 
wherein R is as defined above, and formula (XVI) represents the formula 
These compounds of formulae (XV-a), (XV-b), (XVI-a) and (XVI-b) are compounds which are well known in the field of organic chemistry, and may readily be prepared by any well-known method.
Typical examples of the compounds of the above formula (IV) are as follows:
1-(2-Fluorophenyl)-3-(2-thienyl)-1,3-propanedione,
1-(2-chlorophenyl)-3-(2-thienyl)-1,3-propanedione,
1-(2-trifluoromethylphenyl)-3-(2-thienyl)-1,3-propanedione,
1-(3-chlorophenyl)-3-(2-thienyl)-1,3-propanedione,
1-(3-methylphenyl)-3-(2-thienyl)-1,3-propanedione,
1-(4-fluorophenyl)-3-(2-thienyl)-1,3-propanedione,
1-(4-bromophenyl)-3-(2-thienyl)-1,3-propanedione,
1-(4-iodophenyl)-3-(2-thienyl)-1,3-propanedione,
1-(4-methylphenyl)-3-(2-thienyl)-1,3-propanedione,
1-(4-ethylphenyl)-3-(2-thienyl)-1,3-propanedione,
1-(4-propylphenyl)-3-(2-thienyl)-1,3-propanedione,
1-(4-isopropylphenyl)-3-(2-thienyl)-1,3-propanedione,
1-(4-butylphenyl)-3-(2-thienyl)-1,3-propanedione,
1-(4-tert-butylphenyl)-3-(2-thienyl)-1,3-propanedione,
1-(4-trifluoromethylphenyl)-3-(2-thienyl)-1,3-propanedione,
1-(4-ethoxyphenyl)-3-(2-thienyl)-1,3-propanedione,
1-(4-propoxyphenyl)-3-(2-thienyl)-1,3-propanedione,
1-(4-methylmercaptophenyl)-3-(2-thienyl )-1,3-propanedione,
1-(4-allyloxyphenyl)-3-(2-thienyl)-1,3-propanedione,
1-(4-propargyloxyphenyl)-3-(2-thienyl)-1,3-propanedione,
1-(4-methoxymethylphenyl)-3-(2-thienyl)-1,3-propanedione,
1-(4-ethoxymethylphenyl)-3-(2-thienyl)-1,3-propanedione,
1-(4-methylmercaptomethylphenyl)-3-(2-thienyl)-1,3-propanedione,
1-(4-difluoromethoxyphenyl)-3-(2-thienyl)-1,3-propanedione,
1-(4-trifluoromethoxyphenyl)-3-(2-thienyl)-1,3-propanedione,
1-[4-(2,2,2-trifluoroethoxy)phenyl]-3-(2-thienyl)-1,3-propanedione,
1-[4-(2,2,3,3-tetrafluoropropyloxy)phenyl]-3-(2-thienyl)1,3propanedione,
1-(4-methoxymethoxyphenyl)-3-(2-thienyl)-1,3-propanedione,
1-(4-hydroxyphenyl)-3-(2-thienyl)-1,3-propanedione,
1-(4-phenylphenyl)-3-(2-thienyl)-1,3-propanedione,
1-[4-(4-fluorophenyl)phenyl]-3-(2-thienyl)-1,3-propanedione,
1-[4-(4-methylphenyl)phenyl]-3-(2-thienyl)-1,3-propanedione,
1-(2,4-dichlorophenyl)-3-(2-thienyl)-1,3-propanedione,
1-(3,4-dichlorophenyl)-3-(2-thienyl)-1,3-propanedione,
1-(3,5-dichlorophenyl)-3-(2-thienyl)-1,3-propanedione,
1-(2,6-difluorophenyl)-3-(2-thienyl)-1,3-propanedione,
1-(2,4-difluorophenyl)-3-(2-thienyl)-1,3-propanedione,
1-(3,4-difluorophenyl)-3-(2-thienyl)-1,3-propanedione,
1-(2,4,6-trifluorophenyl)-3-(2-thienyl)-1,3-propanedione,
1-(2,4,6-trichlorophenyl)-3-(2-thienyl)-1,3-propanedione,
1-(2,6-difluoro-4-trifluoromethylphenyl)-3-(2-thienyl)-1,3-propanedione,
1-(4-chlorophenyl)-2-fluoro-3-(2-thienyl)-1,3-propanedione,
1-(4-fluorophenyl)-2-methyl-3-(2-thienyl)-1,3-propanedione,
1-(4-chlorophenyl)-2-methyl-3-(2-thienyl)-1,3-propanedione,
1-(4-chlorophenyl)-2-methyl-3-(2-thienyl)-1,3-propanedione,
1-(4-chlorophenyl)-2-ethyl-3-(2-thienyl)-1,3-propanedione,
1-(4-chlorophenyl)-2-propyl-3-(2-thienyl)-1,3-propanedione,
1-(4-chlorophenyl)-2-methoxymethyl -3-(2 -thienyl)-1,3-propanedione,
1-(4-chlorophenyl)-2-methylmercaptomethyl-3thienyl)3propanedione,
1-(4-chlorophenyl)-2-methylsulinylmethyl-3-(2-thienyl1,3propanedione,
1-(4-chlorophenyl)-2-methylsulfonylmethyl-3-(2thienyl)1,3propanedione,
1-(4-chlorophenyl)-2-(2,2,2-trifluoroethyl)-3-(2-thienyl)-1,3-propanedione, and
1-(4-chlorophenyl)-2-(2,2,3,3-tetrafluoropropyl)-3-(2-thienyl)-1,3-propanedione.
Within the scope of the compound of formula (IV) used as a starting material in the above-described preparation method (b), the compounds of the formula 
wherein R1 and n are as defined above, and R22 represents C1-5 alkyl, C2-6 (total carbon number) alkoxyalkyl, C2-6 (total carbon number) alkylthioalkyl, C2-6 (total carbon number) alkylsulfinylalkyl, C2-6 (total carbon number) alkylsulfonylalkyl or C1-5 haloalkyl, may also be prepared by the preparation method (j) given below.
A method which comprises reacting a compound of the formula 
wherein R1 and n are as defined above, with a compound of the formula
R22xe2x80x94Xxe2x80x83xe2x80x83(XVII)
wherein R22 is as defined above, and X is halogen.
The compounds of the above formula (IV-b) may be prepared by the above-described preparation method (i), and the compounds of the above formula (XVII) are compounds which are well known in the field of organic chemistry.
Typical examples of the compounds of the above formula (IV-a) are as follows:
1-(4-Fluorophenyl)-2-methyl-3-(2-thienyl)-1,3-propanedione,
1-(4-chlorophenyl)-2-methyl-3-(2-thienyl)-1,3-propanedione,
1-(4-chlorophenyl)-2-ethyl-3-(2-thienyl)-1,3-propanedione,
1-(4-chlorophenyl)-2-propyl-3-(2-thienyl)-1,3-propanedione,
1-(4-chlorophenyl)-2-methoxymethyl-3-(2-thienyl)-1,3-propanedione,
1-(4-chlorophenyl)-2-methylmercaptomethyl-3-thienyl)1,3propanedione,
1-(4-chlorophenyl)-2-methylsulfinylmethyl-3-(2-thienyl)1,3propanedione,
1-(4-chlorophenyl)-2-methylsulfonylmethyl-3-(2thienyl)1,3propanedione,
1-(4-chlorophenyl)-2-(2,2,2trifluoroethyl)3(2thienyl)1,3propanedione,and
1-(4-chlorophenyl)-2(2,2,3,3tetrafluoropropyl)-3-(2thienyl)1,3propanedione.
In the above-described preparation method (c), the compound of formula (V) used as a starting material comes under the category of the compounds of formula (I) according to the present invention, and typical examples thereof are shown in Table 1 which will be given later.
The compound of formula (IV) used as the other starting material is a compound which is well known in the field of organic chemistry, and may readily be prepared by any conventionally known method.
In the above-described preparation method (d), when R1 is para-chloro, orthohydroxy or methyl and R2 is hydrogen, the compounds of formulae (VIIa) and (VIIb) used as starting materials are well-known compounds which are described, for example, in references such as Indian J. Chem. Sect., B. 32B(11), p1125-9 (1993); J. Indian Chem. Soc., 68(1), p47-51 (1991); and Arch. Pharm., 329(12), 532-534, 1996. Generally, they may be prepared from a chalcone and a hydrazine according to the procedure described in J. Indian Chem. Soc., 64(7), 408 (1987).
The oxidation reaction of the preparation method (d) may be carried out, for example, according to the procedure described in J. Indian Chem. Soc., 64(7), p408 (1987).
Typical examples of the compounds of the above formula (VIIa) are as follows:
3-(2-Fluorophenyl)-5-(2-thienyl)-pyrazoline,
3-(2-chlorophenyl)-5-(2-thienyl)-pyrazoline,
3-(2-trifluoromethylphenyl)-5-(2-thienyl)-pyrazoline,
3-(3-chlorophenyl)-5-(2-thienyl)-pyrazoline,
3-(4-fluorophenyl)-5-(2-thienyl)-pyrazoline,
3-(4-bromophenyl)-5-(2-thienyl)-pyrazoline,
3-(4-iodophenyl)-5-(2-thienyl)-pyrazoline,
3-(4-ethylphenyl)-5-(2-thienyl)-pyrazoline,
3-(4-propylphenyl)-5-(2-thienyl)-pyrazoline,
3-(4-isopropylphenyl)-5-(2-thienyl)-pyrazoline,
3-(4-butylphenyl)-5-(2-thienyl)-pyrazoline,
3-(4-tert-butylphenyl)-5-(2-thienyl)-pyrazoline,
3-(4-trifluoromethylphenyl)-5-(2-thienyl)-pyrazoline,
3-(4-ethoxyphenyl)-5-(2-thienyl)-pyrazoline,
3-(4-propoxyphenyl)-5-(2-thienyl)-pyrazoline,
3-(4-methylmercaptophenyl)-5-(2-thienyl)-pyrazoline,
3-(4-allyloxyphenyl)-5-(2-thienyl)-pyrazoline,
3-(4-propargyloxyphenyl)-5-(2-thienyl)-pyrazoline,
3-(4-methoxymethylphenyl)-5(2-thienyl)-pyrazoline,
3-(4-ethoxymethylphenyl)-5-(2-thienyl)-pyrazoline,
3-(4-methylmercaptomethylphenyl)-5-(2-thienyl)-pyrazoline,
3-(4-difluoromethoxyphenyl)-5-(2-thienyl)-pyrazoline,
3-(4-trifluoromethoxyphenyl)-5-(2-thienyl)-pyrazoline,
3-[4-(2,2,2-trifluoroethoxy)phenyl]-5-(2-thienyl)-pyrazoline,
3-[4-(2,2,3,3-tetrafluoropropyloxy)phenyl]-5-(2-thienyl)-pyrazoline,
3-(4-methoxymethoxyphenyl)-5-(2-thienyl)-pyrazoline,
3-(4-hydroxyphenyl)-5-(2-thienyl)-pyrazoline,
3-(4-phenylphenyl)-5-(2-thienyl)-pyrazoline,
3-[4-(4-fluorophenyl)phenyl]-5-(2-thienyl)-pyrazoline,
3-[4-(4-methylphenyl)phenyl]-5-(2-thienyl)-pyrazoline,
3 -(2,4-dichlorophenyl)-5-(2-thienyl)-pyrazoline,
3-(3,4-dichlorophenyl)-5-(2-thienyl)-pyrazoline,
3-(3,5-dichlorophenyl)-5-(2-thienyl)-pyrazoline,
3-(2,6-difluorophenyl)-5-(2-thienyl)-pyrazoline,
3-(2,4-difluorophenyl)-5-(2-thienyl)-pyrazoline,
3-(3,4-difluorophenyl)-5-(2-thienyl)-pyrazoline,
3-(2,4,6-trifluorophenyl)-5-(2-thienyl)-pyrazoline,
3-(2,4,6-trichlorophenyl)-5-(2-thienyl)-pyrazoline,
3-(2,6-difluoro-4-trifluoromethylphenyl)-5-(2-thienyl)-pyrazoline,
3-(4-chlorophenyl)-4-fluoro-5-(2-thienyl)-pyrazoline,
3-(4-fluorophenyl)-4-methyl-5-(2-thienyl)-pyrazoline,
3-(4-chlorophenyl)-4-methyl-5-(2-thienyl)-pyrazoline,
3-(4-chlorophenyl)-4-ethyl-5-(2-thienyl)-pyrazoline,
3-(4-chlorophenyl)-4-propyl-5-(2-thienyl)-pyrazoline,
3-(4-chlorophenyl)-4-methoxymethyl-5-(2-thienyl)-pyrazoline,
3-(4-chlorophenyl)-4-methylmercaptomethyl-5-(2-thienyl)-pyrazoline,
3-(4-chlorophenyl)-4-methylsulfinylmethyl-5-(2-thienyl)-pyrazoline,
3-(4-chlorophenyl)-4-methylsulfonylmethyl-5-(2-thienyl)-pyrazoline,
3-(4-chlorophenyl)-4-(2,2,2-trifluoroethyl)-5-(2-thienyl)-pyrazoline,
1-methyl-3-(4-chlorophenyl)-5-(2-thienyl)-pyrazoline,
1-[3-(4-fluorophenyl)-5-(2-thienyl)-4,5-dihydro-1H-pyrazolyl]-1ethanone,
1-[3-(4-chlorophenyl)-5-(2-thienyl)-4,5-dihydro-1H-pyrazolyl]-1ethanone,
1-[3-(4-chlorophenyl)-5-(2-thienyl)-4,5-dihydro-1Hpyrazolyl]1propanoe,
1-[3-(4-chlorophenyl)-5-(2-thienyl)-4,5-dihydro-1H-pyrazolyl]-1butanone,
1[3(4chlorophenyl)5(2thienyl)4,5dihydro1Hpyrazolyl]2methyl1propanoe,
1-[3-(4-chlorophenyl)-5-(2-thienyl)-4,5-dihydro-1Hpyrazolyl]1pentanone,
1[3(4chlorophenyl)5(2thienyl)4,5dihydro1Hpyrazolyl]2,2dimethyl1prope,
1-[3-(4-chlorophenyl)-5-(2-thienyl)-4,5-dihydro-1H-pyrazolyl]-1-none,
1-[3-(4-chlorophenyl)-5-(2-thienyl)-4,5-dihydro-1Hpyrazolyl]2buten1one,
3[3(4chlorophenyl)5(2thienyl)4,5dihydro1Hpyrazolyl](cyclopropyl)methanone,
1-[3-(4-chlorophenyl)-5-(2-thienyl)-4,5-dihydro-1H-pyrazolyl](2,2-difluorocyclopropyl) methanone,
1-[3-(4-chlorophenyl)-5-(2-thienyl)-4,5-dihydro-1H-pyrazolyl]-2-methoxy-1-ethanone,
1[3(4chlorophenyl)5(2thienyl)4,5dihydro1Hpyrazolyl]2(methylmercapto)-1-ethanone,
1[3(4chlorophenyl)5(2thienyl)4,5dihydro1Hpyrazolyl](phenyl)methanone,
1[3(4chlorophenyl)5(2thienyl)4,5dihydro1Hpyrazolyl](4fluorophenyl)methanone,
1[3(4chlorophenyl)5(2thienyl)4,5dihydro1Hpyrazolyl](4trifluoromethylphenyl)methanone,
1-ethylcarbamoyl-3-(4-chlorophenyl)-5-(2-thienyl)-4,5-dihydro-1H-pyrazole,
1-(4-chlorophenyl)carbamoyl-3-(4-chlorophenyl)-5-(2-thienyl)4,5dihydro-1H-pyrazole,
1-ethoxycarbonyl-3-(4-chlorophenyl)-5-(2-thienyl)-4,5-dihydro-1H-pyrazole, and
1-t-butoxycarbonyl-3-(4-chlorophenyl)-5-(2-thienyl)-4,5-dihydro-1H-pyrazole.
Typical examples of the compounds of the above formula (VIIb) are as follows:
5-(2-Fluorophenyl)-3-(2-thienyl)-pyrazoline,
5-(2-chlorophenyl)-3-(2-thienyl)-pyrazoline,
5-(2-trifluoromethylphenyl)-3-(2-thienyl)-pyrazoline,
5-(3-chlorophenyl)-3-(2-thienyl)-pyrazoline,
5-(4-fluorophenyl)-3-(2-thienyl)-pyrazoline,
5-(4-bromophenyl)-3-(2-thienyl)-pyrazoline,
5-(4-iodophenyl)-3-(2-thienyl)-pyrazoline,
5-(4-ethylphenyl)-3-(2-thienyl)-pyrazoline,
5-(4-propylphenyl)-3-(2-thienyl)-pyrazoline,
5-(4-isopropylphenyl)-3-(2-thienyl)-pyrazoline,
5-(4-butylphenyl)-3-(2-thienyl)-pyrazoline,
5-(4-tert-butylphenyl)-3-(2-thienyl)-pyrazoline,
5-(4-trifluoromethylphenyl)-3-(2-thienyl)-pyrazoline,
5-(4-ethoxyphenyl)-3-(2-thienyl)-pyrazoline,
5-(4-propoxyphenyl)-3-(2-thienyl)-pyrazoline,
5-(4-methylmercaptophenyl)-3-(2-thienyl)-pyrazoline,
5-(4-allyloxyphenyl)-3-(2-thienyl)-pyrazoline,
5-(4-propargyloxyphenyl)-3-(2-thienyl)-pyrazoline,
5-(4-methoxymethylphenyl)-3-(2-thienyl)-pyrazoline,
5-(4-ethoxymethylphenyl)-3-(2-thienyl)-pyrazoline,
5-(4-methylmercaptomethylphenyl)-3-(2-thienyl)-pyrazoline,
5-(4-difluoromethoxyphenyl)-3(2-thienyl)-pyrazoline,
5-(4-trifluoromethoxyphenyl)-3-(2-thienyl)-pyrazoline,
5-[4-(2,2,2-trifluoroethoxy)phenyl]3-(2-thienyl)-pyrazoline,
5-[4-(2,2,3,3-tetrafluoropropyloxy)phenyl]-3-(2-thienyl)-pyrazoline,
5-(4-methoxymethoxyphenyl)-3-(2-thienyl)-pyrazoline,
5-(4-hydroxyphenyl)-3-(2-thienyl)-pyrazoline,
5-(4-phenylphenyl)-3-(2-thienyl)-pyrazoline,
5-[4-(4-fluorophenyl)phenyl]-3-(2-thienyl)-pyrazoline,
5-[4-(4-methylphenyl)phenyl]-3-(2-thienyl)-pyrazoline,
5-(2,4-dichlorophenyl)-3-(2-thienyl)-pyrazoline,
5-(3,4-dichlorophenyl)-3-(2-thienyl)-pyrazoline,
5-(3,5-dichlorophenyl)-3-(2-thienyl)-pyrazoline,
5-(2,6-difluorophenyl)-3-(2-thienyl)-pyrazoline,
5-(2,4-difluorophenyl)-3-(2-thienyl)-pyrazoline,
5-(3,4-difluorophenyl)-3-(2-thienyl)-pyrazoline,
5-(2,4,6-trifluorophenyl)-3-(2-thienyl)-pyrazoline,
5-(2,4,6-trichlorophenyl)-3-(2-thienyl)-pyrazoline,
5-(2,6-difluoro-4-trifluoromethylphenyl)-3-(2-thienyl)-pyrazoline,
5-(4-chlorophenyl)-4-fluoro-3-(2-thienyl)-pyrazoline,
5-(4-fluorophenyl)-4-methyl-3-(2-thienyl)-pyrazoline,
5-(4-chlorophenyl)-4-methyl-3-(2-thienyl)-pyrazoline,
5-(4-chlorophenyl)-4-ethyl-3-(2-thienyl)-pyrazoline,
5-(4-chlorophenyl)-4-propyl-3-(2-thienyl)-pyrazoline,
5-(4-chlorophenyl)-4-methoxymethyl-3-(2-thienyl)-pyrazoline,
5-(4-chlorophenyl)-4-methylmercaptomethyl-3-(2-thienyl)-pyrazoline,
5-(4-chlorophenyl)-4-methylsulfinylmethyl-3-(2-thienyl)-pyrazoline,
5-(4-chlorophenyl)-4-methylsulfonylmethyl-3-(2-thienyl)-pyrazoline,
5-(4-chlorophenyl)-4-(2,2,2-trifluoroethyl)-3-(2-thienyl)-pyrazoline,
5-(4-chlorophenyl)-4-(2,2,3,3-tetrafluoropropyl)-3-(2-thienyl)-pyrazoline,
1-methyl-5-(4-chlorophenyl)-3-(2-thienyl)-pyrazoline,
1-[5-(4-fluorophenyl)-3-(2-thienyl)-4,5-dihydro-1H-pyrazolyl]-1ethanone,
1-[5-(4chlorophenyl)-3-(2-thienyl)-4,5-dihydro-1H-pyrazolyl]-1ethanone,
1-[5-(4-chlorophenyl)-3-(2-thienyl)-4,5-dihydro-1Hpyrazolyl]1propanone,
1-[5-(4-chlorophenyl)-3-(2-thienyl)-4,5-dihydro-1H-pyrazolyl]-1butanone,
1[5(4chlorophenyl)3(2thienyl)4,5dihydro1Hpyrazolyl]2methyl1propanoe,
1-[5-(4-chlorophenyl)-3-(2-thienyl)-4,5-dihydro-1Hpyrazolyl]1pentanone,
1-[5-(4-chlorophenyl)-3-(2-thienyl)-4,5-dihydro-1Hpyrazolyl]2,2dimethyl-1-propanone,
1-[5-(4-chlorophenyl)-3-(2-thienyl)-4,5-dihydro-1H-pyrazolyl]1hexanone,
1-[5-(4-chlorophenyl)-3-(2-thienyl)-4,5-dihydro-1H-pyrazolyl]-2-buten-1-one,
1[5(4chlorophenyl)3(2thienyl)4,5dihydro1Hpyrazolyl](cyclopropyl)-methanone,
1[5(4chlorophenyl)3(2thienyl)4,5dihydro1Hpyrazolyl](2,2difluorocyclopropyl)methanone,
1-[5-(4-chlorophenyl)-3-(2-thienyl)-4,5-dihydro-1H-pyrazolyl]-2-methoxy-1-ethanone,
1[5(4chlorophenyl)3(2thienyl)4,5dihydro1Hpyrazolyl]2methylmercapto1-ethanone,
1[5(4chlorophenyl)3(2thienyl)4,5dihydro1Hpyrazolyl](phenyl)methanone
1[5(4chlorophenyl)3(2thienyl)4,5dihydro1Hpyrazolyl](4fluorophenyl)methanone,
1-[5-(4-chlorophenyl)-3-(2-thienyl)-4,5-dihydro-1H-pyrazolyl](4-trifluoromethylphenyl) methanone,
1-ethylcarbamoyl-5-(4-chlorophenyl)-3-(2-thienyl)-pyrazoline,
1-(4-chlorophenyl)carbamoyl-5-(4-chlorophenyl)-3-(2-thienyl)pyrazoline,
1-ethoxycarbonyl-5-(4-chlorophenyl)-3-(2-thienyl)-pyrazoline, and
1-t-butoxycarbonyl-5-(4-chlorophenyl)-3-(2-thienyl)-pyrazoline.
The compound of formula (VIII) used as the starting material in the above-described preparation method (e) may be prepared by the preparation method (a), (b), (c) or (d).
A typical example of the compound of the above formula (VIII) is as follows:
3-(4-Chlorophenyl)-4-methylmercaptomethyl-5-(2-thienyl)-1H-pyrazole.
Typical examples of the compounds of the above formula (IX) which are obtained by oxidizing a compound of the above formula (VIII) are as follows:
3-(4-Chlorophenyl)-4-methylsulfinylmethyl-5-(2-thienyl)-1H-pyrazole, and
3-(4-chlorophenyl)-4-methylsulfonylmethyl-5-(2-thienyl)-1H-pyrazole.
As described previously, all of the compounds of formulae (II), (IV), (X) and (XI) used as starting materials in the above-described preparation methods (a), (b), (f) and (g) are novel compounds. These compounds, which are novel intermediates according to the present invention, can be represented by the following formula: 
wherein Q is 
and, R1, R2 and n are as defined above, with the exception of the cases in which Q is 
and R1 is para-chloro.
Moreover, the compounds of formulae (VIIa) and (VIIb) used as starting materials in the above-described preparation methods (d) are novel compounds, with the exception of the cases in which R1 is para-chloro, ortho-hydroxy or methyl and R2 is hydrogen. These compounds, which are novel intermediates according to the present invention, can be represented by the following formula: 
wherein R11 represents halogen, C1-6 alkyl, C1-5 haloalkyl, C2-6 alkoxy, C1-4 alkylthio, C2-5 alkenyloxy, C3-5 alkynyloxy, C2-6 (total carbon number) alkoxyalkyl, C2-6 (total carbon number) alkylthioalkyl, C1-5 haloalkoxy, C2-6 (total carbon number) alkoxyalkoxy, hydroxy or optionally substituted phenyl, and R2, R3 and n are as defined above,
with the exception of the cases in which R1 is para-chloro, ortho-hydroxy or methyl and R2 is hydrogen.
The reaction of the above-described preparation method (a) may be carried out in a suitable diluent. Examples of the diluents which may be used for this purpose include water; aliphatic, alicyclic and aromatic hydrocarbons (which may optionally be chlorinated) such as pentane, hexane, cyclohexane, petroleum ether, ligroine, benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene and dichlorobenzene; ethers such as ethyl ether, methyl ethyl ether, isopropyl ether, butyl ether, dioxane, dimethoxyethane (DME), tetrahydrofuran, (THF) and diethylene glycol dimethyl ether (DGM); nitrites such as acetonitrile, propionitrile and acrylonitrile; alcohols such as methanol, ethanol, isopropanol, butanol and ethylene glycol; and acid amides such as dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and hexamethylphosphoric triamide (HMPA).
The reaction of the preparation method (a) may be carried out in the presence of an acid catalyst. Examples of the acid catalysts which may be used for this purpose include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid and sodium hydrogen sulfite; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; organic amine hydrochlorides such as pyridine hydrochloride and triethylamine hydrochloride; amine sulfonates such as pyridine p-toluenesulfonate and triethylamine sulfonate.
Although the preparation method (a) may be carried out within a substantially wide temperature range, it is generally suitable to employ a temperature in the range of about xe2x88x9220 to about 150, and preferably about 20 to about 120. Moreover, the reaction should desirably be carried out under atmospheric pressure, but it may optionally be operated under an elevated or reduced pressure.
In carrying out the preparation method (a), the desired compound can be obtained, for example, by reacting a 1 mole of the compound of formula (II) with 1 to 5 moles of the compound of formula (III) in a diluent such as ethanol and in the presence of pyridine p-toluenesulfonate.
The reaction of the above-described preparation method (b) may be carried out in a suitable diluent. Examples of the diluents, which may be used for this purpose include water; aliphatic, alicyclic and aromatic hydrocarbons (which may optionally be chlorinated) such as pentane, hexane, cyclohexane, petroleum ether, ligroine, benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene and dichlorobenzene; ethers such as ethyl ether, methyl ethyl ether, isopropyl ether, butyl ether, dioxane, dimethoxyethane (DME), tetrahydrofuran (THF) and diethylene glycol dimethyl ether (DGM); nitriles such as acetonitrile, propionitrile and acrylonitrile; alcohols such as methanol, ethanol, isopropanol, butanol and ethylene glycol; and acid amides such as dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and hexamethylphosphoric triamide (HMPA).
The reaction of the preparation method (b) may be carried out in the presence of an acid catalyst. Examples of the acid catalysts which may be used for this purpose include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid and sodium hydrogen sulfite; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; organic amine hydrochlorides such as pyridine hydrochloride and triethylamine hydrochloride; amine sulfonates such as pyridine p-toluenesulfonate and triethylamine sulfonate.
Although the preparation method (b) may be carried out within a substantially wide temperature range, it is generally suitable to employ a temperature in the range of about xe2x88x9220 to about 150, and preferably about 20 to about 120. Moreover, the reaction should desirably be carried out under atmospheric pressure, but it may optionally be operated under an elevated or reduced pressure.
In carrying out the preparation method (b), the desired compound can be obtained, for example, by reacting a 1 mole of the compound of formula (IV) with 1 to 5 moles of the compound of formula (III) in a diluent such as ethanol and in the presence of pyridine p-toluenesulfonate.
The reaction of the above-described preparation method (c) may be carried out in a suitable diluent. Examples of the diluents which may be used for this purpose include aliphatic, alicyclic and aromatic hydrocarbons (which may optionally be chlorinated) such as pentane, hexane, cyclohexane, petroleum ether, ligroine, benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene and dichlorobenzene; ethers such as ethyl ether, methyl ethyl ether, isopropyl ether, butyl ether, dioxane, dimethoxyethane (DME), tetrahydrofuran (THF) and diethylene glycol dimethyl ether (DGM); nitriles such as acetonitrile, propionitrile and acrylonitrile; alcohols such as methanol, ethanol, isopropanol, butanol and ethylene glycol; esters such as ethyl acetate and amyl acetate; acid amides such as dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and hexamethylphosphoric triamide (HMPA); and sulfones and sulfoxides such as dimethyl sulfoxide (DMSO) and sulfolane.
The reaction of the preparation method (c) may be carried out in the presence of an acid binding agent. Examples of the acid binding agents which may be used for this purpose include inorganic bases, i.e. hydrides, hydroxides, carbonates and bicarbonates of alkali metals and alkaline earth metals, such as sodium hydride, lithium hydride, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide; and organic bases, i.e. alcoholates, tertiary amines, dialkylaminoanilines and pyridines, such as triethylamine, 1,1,4,4-tetramethylethylene-diamine (TMEDA), N,N-dimethylaniline, N,N-diethylaniline, pyridine, 4-dimethylaminopyridine (DMAP),1,4-diazabicyclo [2.2.2]octane (DABCO) and 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU).
Although the preparation method (c) may be carried out within a substantially wide temperature range, it is generally suitable to employ a temperature in the range of about xe2x88x9250 to about 150 and preferably about xe2x88x9220 to about 100. Moreover, the reaction should-desirably be carried out under atmospheric pressure, but it may optionally be operated under an elevated or reduced pressure.
In carrying out the preparation method (c), the desired compound can be obtained, for example, by reacting a 1 mole of the compound of formula (V) with 1 to 5 moles of the compound of formula (VI) in a diluent such as tetrahydrofuran and in the presence of sodium hydride.
The reaction of the above-described preparation method (d) may be carried out in a suitable diluent. Examples of the diluents which may be used for this purpose include aliphatic, alicyclic and aromatic hydrocarbons (which may optionally be chlorinated) such as pentane, hexane, cyclohexane, petroleum ether, ligroine, benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene and dichlorobenzene.
In the preparation method (d), the oxidation of the compound of formula (VIIa) or (VIIb) is carried out in the presence of an oxidizing agent. Usable oxidizing agents include, for example, manganese dioxide, lead oxide, mercury oxide, silver nitrate and lead tetraacetate.
Although the preparation method (d) may be carried out within a substantially wide temperature range, it is generally suitable to employ a temperature in the range of about xe2x88x9220 to about 200, and preferably about 20 to about 150 . Moreover, the reaction should desirably be carried out under atmospheric pressure, but it may optionally be operated under an elevated or reduced pressure.
In carrying out the preparation method (d), the desired compound can be obtained, for example, by reacting a 1 mole of the compound of formula (VIIa) or (VIIb) with 3 to 10 moles of an oxidizing agent such as manganese dioxide, in a diluent such as toluene.
The reaction of the above-described preparation method (e) may be carried out in a suitable diluent. Examples of the diluents which may be used for this purpose include water; aliphatic, alicyclic and aromatic hydrocarbons (which may optionally be chlorinated) such as pentane, hexane, cyclohexane, petroleum ether, ligroine, benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene and dichlorobenzene; ethers such as ethyl ether, methyl ethyl ether, isopropyl ether, butyl ether, dioxane, dimethoxyethane (DME), tetrahydrofuran (THF) and diethylene glycol dimethyl ether (DGM); and alcohols such as methanol, ethanol, isopropanol, butanol and ethylene glycol.
The oxidizing agents which may be used to oxidize the compound of formula (VIII) in the preparation method (e) include, for example, hydrogen peroxide, sodium periodate and m-chloroperbenzoic acid.
Although the preparation method (c) may be carried out within a substantially wide temperature range, it is generally suitable to employ a temperature in the range of about xe2x88x9250 to about 200, and preferably about xe2x88x9220 to about 100. Moreover, the reaction should desirably be carried out under atmospheric pressure, but it may optionally be operated under an elevated or reduced pressure.
In carrying out the preparation method (e), the desired compound can be obtained, for example, by reacting a 1 mole of the compound of formula (VIII) with 1 to 5 moles of m-chloroperbenzoic acid in a diluent such as dichloromethane.
The reaction of the above-described preparation method (f) may be carried out in a suitable diluent. Examples of the diluents which may be used for this purpose include water; aliphatic, alicyclic and aromatic hydrocarbons (which may optionally be chlorinated) such as pentane, hexane, cyclohexane, petroleum ether, ligroine, benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene and dichlorobenzene; ethers such as ethyl ether, methyl ethyl ether, isopropyl ether, butyl ether, dioxane, dimethoxyethane (DME), tetrahydrofuran (THF) and diethylene glycol dimethyl ether (DGM); ketones such as acetone, methyl ethyl ketone (MEK), methyl isopropyl ketone and methyl isobutyl ketone (MIBK); nitriles such as acetonitrile, propionitrile and acrylonitrile; esters such as ethyl acetate and amyl acetate; acid amides such as dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and hexamethylphosphoric triamide (HMPA); and sulfoxides such as dimethyl sulfoxide (DMSO).
The oxidizing agents which may be used to oxidize the compound of formula (X) in the preparation method (f) include, for example, manganese dioxide, Jones"" reagent and pyridinium dichromate (PDC).
Although the preparation method (f) may be carried out within a substantially wide temperature range, it is generally suitable to employ a temperature in the range of about xe2x88x9220 to about 200 and preferably about 0 to about 120. Moreover, the reaction should desirably be carried out under atmospheric pressure, but it may optionally be operated under an elevated or reduced pressure.
In carrying out the preparation method (f), the desired compound can be obtained, for example, by reacting a 1 mole of the compound of formula (X) with 1 to 10 moles of an oxidizing agent (e.g., PDC) in a diluent such as dichloromethane.
The reaction of the above-described preparation method (g) may be carried out in a suitable diluent. Examples of the diluents which may be used for this purpose include water; aliphatic, alicyclic and aromatic hydrocarbons (which may optionally be chlorinated) such as pentane, hexane, cyclohexane, petroleum ether, ligroine, benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene and dichlorobenzene; ethers such as ethyl ether, methyl ethyl ether, isopropyl ether, butyl ether, dioxane, dimethoxyethane (DME), tetrahydrofuran (THF) and diethylene glycol dimethyl ether (DGM); alcohols such as methanol, ethanol, isopropanol, butanol and ethylene glycol; and esters such as ethyl acetate and amyl acetate.
The reaction of the preparation method (g) may be carried out in the presence of an acid binding agent. Examples of the acid binding agents which may be used for this purpose include inorganic bases, i.e. hydrides, hydroxides, carbonates and bicarbonates of alkali metals and alkaline earth metals, such as sodium hydride, lithium hydride, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide.
The reaction of the preparation method (g) may be carried out in the presence of a catalyst. Examples of the catalysts which may be used for this purpose include tetrakistriphenylphosphine palladium.
The above-described preparation method (g) may also be carried out by using a phase-transfer catalyst. Examples of the diluents which may be used for this purpose include water; aliphatic, alicyclic and aromatic hydrocarbons (which may optionally be chlorinated) such as pentane, hexane, cyclohexane, petroleum ether, ligroine, benzene, toluene, xylene, dichloromethane, chlorobenzene and dichlorobenzene; and ethers such as ethyl ether, methyl ethyl ether, isopropyl ether, butyl ether, dioxane, dimethoxyethane (DME), tetrahydrofuran (THF) and diethylene glycol dimethyl ether (DGM).
Examples of usable phase-transfer catalysts include quaternary ions such as tetramethylammonium bromide, tetrapropylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium bissulfate, tetrabutylammonium iodide, trioctylmethylammonium chloride, benzyltriethylammonium bromide, butylpyridinium bromide, heptylpyridinium bromide and benzyltriethylammonium chloride; crown ethers such as dibenzo-18-crown-6, dicyclohexyl-18-crown-6 and 18-crown-6; and cryptands such as [2.2.2]-cryptate, [2.1.1]-cryptate, [2.2.1]-cryptate, [2.2.B]-cryptate, [20202S]-cryptate and [3.2.2]-cryptate.
Although the preparation method (g) may be carried out within a substantially wide temperature range, it is generally suitable to employ a temperature in the range of about 0 to about 200 and preferably about 0 to about 120. Moreover, the reaction should desirably be carried out under atmospheric pressure, but it may optionally be operated under an elevated or reduced pressure.
In carrying out the preparation method (g), the desired compound can be obtained, for example, by reacting a 1 mole of the compound of formula (XI) with 1 to 5 moles of the compound of formula (XII) in a diluent such as benzene) and in the presence of tetrakistriphenylphosphine palladium.
The reaction of the above-described preparation method (h) may be carried out in a suitable diluent. Examples of the diluents which may be used for this purpose include aliphatic, alicyclic and aromatic hydrocarbons such as pentane, hexane, cyclohexane, petroleum ether, ligroine, benzene, toluene and xylene; and ethers such as ethyl ether, methyl ethyl ether, isopropyl ether, butyl ether, dioxane, dimethoxyethane (DME), tetrahydrofuran (THF) and diethylene glycol dimethyl ether (DGM).
The reaction of the preparation method (h) may be carried out in the presence of an organometallic reagent. Examples of the organometallic reagents which may be used for this purpose include organolithium compound such as methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, phenyllithium, dimetylcopper-lithium, lithium diisopropylamide, lithium cyclohexylisopropylamide, lithium dicyclohexylamide, n-butyllithium DABCO, n-butyllithium DBU and n-butyllithium TMEDA; and organic Grignard reagents such as methylmagnesium bromide, ethylmagnesium iodide and n-propylmagnesium bromide.
Although the preparation method (h) may be carried out within a substantially wide temperature range, it is generally suitable to employ a temperature in the range of about xe2x88x92100 to about 50 and preferably about xe2x88x9280 to about 25. Moreover, the reaction should desirably be carried out under atmospheric pressure, but it may optionally be operated under an elevated or reduced pressure.
In carrying out the preparation method (h), the desired compound can be obtained, for example, by reacting a 1 mole of the compound of formula (XIII) with 1 to 3 moles of the compound of formula (XIV) in a diluent such as tetrahydrofuran and in the presence of n-butyllithium.
The reaction of the above-described preparation method (i) may be carried out in a suitable diluent. Examples of the diluents which may be used for this purpose include aliphatic, alicyclic and aromatic hydrocarbons such as pentane, hexane, cyclohexane, petroleum ether, ligroine, benzene, toluene, xylene; ethers such as ethyl ether, methyl ethyl ether, isopropyl ether, butyl ether, dioxane, dimethoxyethane (DME), tetrahydrofuran (THF) and diethylene glycol dimethyl ether (DGM); alcohols such as methanol, ethanol, isopropanol, butanol and ethylene glycol; and acid amides such as dimethylfomamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and hexamethylphosphoric triamide (HMPA).
The reaction of the preparation method (i) may be carried out in the presence of an acid binding agent. Examples of the acid binding agents which may be used for this purpose include inorganic bases, i.e. hydrides, hydroxides, carbonates and bicarbonates of alkali metals and alkaline earth metals, such as sodium hydride, lithium hydride, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, lithium hydroxide, sodiummetal amides such as lithium amide, sodium amide and potassium amide; and hydroxide, potassium hydroxide and calcium hydroxide; inorganic alkali organic bases such as alcoholates.
Although the preparation method (i) may be carried out within a substantially wide temperature range, it is generally suitable to employ a temperature in the range of about xe2x88x9220 to about 200 and preferably about 20 to about 150. Moreover, the reaction should desirably be carried out under atmospheric pressure, but it may optionally be operated under an elevated or reduced pressure.
In carrying out the preparation method (i), the desired compound can be obtained, for example, by reacting a 1 mole of the compound of formula (XV-a) with 1 to 1.5 moles of the compound of formula (XVI-b) in a diluent such as tetrahydrofuran and in the presence of sodium hydride.
The reaction of the above-described preparation method (j) may be carried out in a suitable diluent. Examples of the diluents which may be used for this purpose include water; aliphatic, alicyclic and aromatic hydrocarbons (which may optionally be chlorinated) such as pentane, hexane, cyclohexane, petroleum ether, ligroine, benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene and dichlorobenzene; ethers such as ethyl ether, methyl ethyl ether, isopropyl ether, butyl ether, dioxane, dimethoxyethane (DME), tetrahydrofuran (THF) and diethylene glycol dimethyl ether (DGM); ketones such as acetone, methyl ethyl ketone (MEK), methyl isopropyl ketone and methyl isobutyl ketone (MIBK); nitriles such as acetonitrile, propionitrile and acrylonitrile; esters such as ethyl acetate and amyl acetate; acid amides such as dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and hexamethylphosphoric triamide (HMPA); sulfones and sulfoxides such as dimethyl sulfoxide (DMSO) and sulfolane; and bases such as pyridine.
The reaction of the preparation method (j) may be carried out in the presence of an acid binding agent. Examples of the acid binding agents which may be used for this purpose include inorganic bases, i.e. hydrides, hydroxides, carbonates and bicarbonates of alkali metals and alkaline earth metals, such as sodium hydride, lithium hydride, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide; inorganic alkali metal amides such as lithium amide, sodium amide and potassium amide; organic bases, i.e. alcoholates, tertiary amines, dialkylaminoanilines and pyridines such as triethylamine,1,1,4,4tetramethylethylenediamine (TMEDA), N,N-dimethylaniline, N,N-diethylaniline, pyridine, 4-dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2.2.2]octane (DABCO) and 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU); and organolithium compound such as methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, phenyllithium, dimethylcopper-lithium, lithium diisopropylamide, lithium cyclohexylisopropylamide, lithium dicyclohexylamide, n-butyllithium DABCO, n-butyllithium DBU and n-butyllithium TMEDA; and organic Grignard reagents such as methylmagnesium bromide, ethylmagnesium iodide and n-propylmagnesium bromide.
The above-described preparation method (j) may also be carried out by using a phase-transfer catalyst. Examples of the diluents which may be used for this purpose include water; aliphatic, alicyclic and aromatic hydrocarbons (which may optionally be chlorinated) such as pentane, hexane, cyclohexane, petroleum ether, ligroine, benzene, toluene, xylene, dichloromethane, chlorobenzene and dichlorobenzene; and ethers such as ethyl ether, methyl ethyl ether, isopropyl ether, butyl ether, dioxane, dimethoxyethane (DME), tetrahydrofuran (THF) and diethylene glycol dimethyl ether (DGM).
Examples of usable phase-transfer catalysts include quaternary ions such as tetramethylammonium bromide, tetrapropylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium bissulfate, tetrabutylammonium iodide, trioctylmethylammonium chloride, benzyltriethylammonium bromide, butylpyridinium bromide, heptylpyridinium bromide and benzyltriethylammonium chloride; crown ethers such as dibenzo-18-crown-6, dicyclohexyl-18-crown-6 and 18-crown-6; and cryptands such as [2.2.2]-cryptate, [2.1.1]-cryptate, [2.2.1]-cryptate, [2.2.B]-cryptate, [20202S]-cryptate and [3.2.2]-cryptate.
Although the preparation method (j) may be carried out within a substantially wide temperature range, it is generally suitable to employ a temperature in the range of about xe2x88x9250 to about 200 and preferably about xe2x88x9220 to about 100. Moreover, the reaction should desirably be carried out under atmospheric pressure, but it may optionally be operated under an elevated or reduced pressure.
In carrying out the preparation method (j), the desired compound can be obtained, for example, by reacting a 1 mole of the compound of formula (IV-b) with 1 to 5 moles of the compound of formula (XVII) in a diluent such as tetrahydrofuran and in the presence of sodium hydride.
The compounds of formula (I) according to the present invention manifest a powerful nematicidal action and anthelmintic action. Accordingly, they can be used as nematicides and anthelmintics. Moreover, the active compounds of formula (I) according to the present invention exhibit a proper controlling effect on noxious nematodes without causing phytotoxicity to cultivated plants, and on parasites without causing toxicity to mammals.
Examples of the nematodes to which the compounds of formula (I) according to the present invention, can be applied include as follows, but are not limited thereto; root-lesion nematodes (Pratylenchus spp.), potato cyst nematode (Globodera rostochiensis Wollenweber), soybean cyst nematode (Heterodera glycines Ichinohe), root-knot nematodes (Meloidogyne spp.), rice heart nematode (Aphelenchoides besseyi Christie) and pine nematode (Bursaphelenchus xylophilus).
Examples of the parasites to which the compounds of the formula (I) according to the present invention can be applied include as follows, but not limited thereto;
Parasites of cattle and sheep:
twisted stomach worm (Mecistocirrus spp., Haemonchus spp.)
stomach worm (Ostertagia spp.)
esophagus worm (Gongylonema spp.)
hair worm (Cooperia spp., Nematodirus spp., Trichosrongylus spp.)
nodular worm (Oesophagostomum spp.)
hook worm (Bunostomum spp.)
tape worm (Moniezia spp., Taenia spp.)
lung worm (Dicyocaulus spp.)
liver fluke (Fasciola spp.)
pancreas fluke (Eurytreama spp.)
fluke (Paramphistomum spp., Fischoederius spp., Gasrtothylax spp.)
Parasites of horse:
tape worm (Anoplocephala spp., Paranoplocephala spp.)
strongylida (Strongylus spp., Triodontophorus spp., Oerophagodontus spp., Trichonema spp., Poteriostomum spp., Cylicocyclus spp., Cyliodontophorus spp.)
filaria (Setaria spp.)
pin worm (Oxyuris spp.)
round worm (Parascaris spp.)
stomach worm (Habronema spp.)
Parasites of swine:
round worm (Ascaris spp.)
hook worm (Necator spp., Globocephalus spp.)
nodular worm (Oesophagostomum spp.)
trichinella (Trichinella spp.)
macracanthorhynchus (Macracanthorhynchus spp.)
gnathostoma (Gnathostoma spp.)
kidney worm (Stephanurus spp., Dioctohphyme spp.)
lung worm (Metastrongylus spp., Choerostrongylus spp.)
Parasites of dog:
round worm (Toxocala spp. Toxascaris spp.)
hook worm (Uncinaria spp. Ancylostoma spp.)
whip worm (Trichocephalus spp.)
thelazia (Thelazia spp.)
heart worm (Dirofilaria spp.)
trichinella (Trichinella spp.)
tape worm (Diphyllobotrium spp., Mesocestoides spp., Taenia spp., Echinococcus spp. Dipylidium spp., Multiceps spp.)
fluke (Echinocasmus spp., Plagiorchis spp., Heterophyes spp., Metagonimus spp)
Parasites of cat:
round worm (Toxoxala spp.)
Parasites of chicken:
round worm (Ascaridia spp.)
hair worm (Capillaria spp.)
cecal worm (Heterakis spp.)
tape worm (Raillietina spp., Hymenolepis spp.)
fluke (Echinoparyphium spp., Echinostoma spp., Catatropis spp., Prosthogonimus spp, Metorchis spp.)
gape worm (Syngamus spp.)
Parasites of fish:
monogenea (Gyrodactylus spp., Dactylogyrus spp.)
Parasites of human
round worm (Ascaris spp.)
pin worm (Enterobius spp.)
hook worm (Ancylostama spp., Necator spp.)
whip worm (Trichocephalus spp.)
hair worm (Trichostrongylus spp.)
filaria (Brugia spp., Wuchereria spp., Onchocerca spp.)
tape worm (Diphyllobothrium spp.; Diplogonoporus spp., Taenia spp.,
Raillietina spp., Taeniarynchus spp.)
schistosoma (Schistosoma spp.)
lung fluke (Paragonimus spp.)
liver fluke (Clonorchis spp.)
The active compounds of formula (I) according to the present invention, in a case where the active compounds are used as nematicides, can be present in their commercially available formulations and in the use forms prepared from these formulations, as a mixture with other active compounds such as insecticides, sterilizing agents, acaricides or fungicides. The aforesaid insecticides include, for example, organic phosphates, carbamates, carboxylates, chlorinated hydrocarbons, chloronicotinyl compounds, and insecticidal substances produced by microorganisms.
The active compounds of formula (I) according to the present invention can further be present in their commercially available formulations and in the use forms prepared from these formulations, as a mixture with synergistic agents. Synergistic agents are compounds which increase the action of the active compounds, without it being necessary for the synergistic agent added to be active itself.
The content of the active compounds of formula (I) according to the present invention in their commercially available use forms can vary within wide limits. The concentration of the active compounds of formula (I) according to the present invention in their use forms can be from 0.000001 to 100% by weight, preferably between 0.00001 to 1% by weight.
The active compounds of the present invention can be converted into customary formulations, such as solution, emulsions, wettable powder, suspension, powder, foam, paste, granule, natural and synthetic materials impregnated with active compounds, microcapsule, coating composition for seeds, and fumigant, liquid, pill, tablet and capsul.
These formulations may be produced in the manner known per se, for example, lay mixing an active compound with extenders, i.e. liquid diluents, liquefied gas diluents, solid diluents or carriers, optionally with the use of surface-active agents, i.e. emulsifying agents and/or dispersing agents and/or foam-forming agents. In the case of the use of water as an extender, organic solvents, for example, may be used as auxiliary solvents.
As liquid diluents or carriers, there may be used, for example, aromatic hydrocarbons such as xylene, toluene and alkylnaphthalenes; chlorinated aromatic and chlorinated aliphatic hydrocarbons such as chlorobenzenes, chloroethylenes and methylene chloride; aliphatic hydrocarbons such as cyclohexane and paraffins (for example, mineral oil fractions); alcohols such as butanol, glycol, and their ethers and esters; ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and cyclohexanone; strongly polar solvents such as dimethylformamide and dimethyl sulfoxide; as well as water.
By liquefied gaseous diluents or carriers are meant liquids which would be gaseous at normal temperature and normal pressure, for example, aerosol propellants such as butane, propane, nitrogen gas, carbon dioxide and halogenated hydrocarbons.
As solid diluents, there may be used, for example, ground natural minerals such as kaolins, clays, talc, chalk, quartz, attapulgite, montmorillonite and diatomaceous earth; and ground synthetic minerals such as highly-dispersed silicic acid, alumina and silicates.
As solid carriers for granules, there may be used, for example, crushed and fractionated natural rocks suck as calcite, marble, pumice, sepiolite and dolomite; synthetic granules of inorganic or organic meals; and granules of organic materials such as sawdust, coconut shells, maize cobs and tobacco stalks.
As emulsifying and/or foam-forming agents, there are may be used, for example, non-ionic and anionic emulsifiers such as polyoxyethylene-fatty acid esters, polyoxyethylene-fatty alcohol esters (for example, alkylaryl polyglycol ethers, alkylsulfonates, alkylsulfates and arylsulfates) and albumin hydrolysis products. Usable dispersing agents include, for example, lignin sulfite waste liquors and methylcellulose.
Adhesives may also be used in formulations such as powders, granules and emulsions. Usable adhesives include, for example, carboxymethylcellulose, and natural and synthetic polymers such as gum arabic, polyvinyl alcohol and polyvinyl acetate.
It is possible to use colorants including, for example, inorganic pigments (for example, iron oxide, titanium oxide and Prussian Blue); organic dyestuffs such as alizarin dyestuffs, azo dyestuffs and metal phthalocyanine dyestuffs; and trace elements such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc.
The formulations can generally contain 0.1 to 95% by weight, preferably 0.5 to 90% by weight, of the aforesaid active compounds.
Now, the preparation and use of compounds in accordance with the present invention are more specifically explained with reference to the following examples. However, it is to be understood that the present invention is not limited thereto. Unless otherwise specified, all parts are by weight.